KR20030046609A - A PROCESS FOR THE PREPARATION OF β-D-RIBOFURANOSE DERIVATIVES - Google Patents

Abstract

PURPOSE: A process for preparing beta-di-ribofuranose derivatives is provided, thereby preparing the high purity beta-di-ribofuranose derivatives useful as intermediates of ribavirin in higher yield. CONSTITUTION: A process for preparing beta-di-ribofuranose derivatives comprises reacting a compound of formula(2) and a compound of formula(3) in the presence of a catalyst selected from methane sulfonic acid, benzene sulfonic acid and para-toluene sulfonic acid at 80 to 120 deg. C, and crystallizing the reaction product in a solvent to prepare beta-di-ribofuranose derivatives of formula(1), wherein R1 is hydroxy protecting group; R2 is C1-C4 lower alkyl; and the crystallizing solvent is selected from the group consisting of methanol, ethanol, butanol, isobutanol, methanol solution, ethanol solution, butanol solution and isobutanol solution.

Description

A process for producing beta-di-ribofuranose derivatives {A PROCESS FOR THE PREPARATION OF β-D-RIBOFURANOSE DERIVATIVES}

The present invention relates to a method for preparing a compound of formula (I) useful as an intermediate of ribavirin having antiviral action.

In the above formula, R ¹ represents a hydroxy protecting group, and R ² represents a lower alkyl group of C ₁ to C ₄ .

Compound (1) is a compound useful as an intermediate of ribavirin (ribavirin) having an antiviral action, the conventional preparation method is US Patent No. 3,798,209 and J. Med. Chem., 1972, Vol. 15, No. 11, and 1150-1154 are known. The preparation method disclosed in US Pat. No. 3,798,209 is shown in Scheme 1 below.

In the above scheme, Bz represents a benzoyl group.

However, the manufacturing method disclosed in the above-mentioned 3,798, 209 has a problem that not only the reaction time is very long, but also a separate separation process is required because the compound of Formula 1 '' is generated together as a byproduct. In addition, in order to perform the separation process, the fractional crystallization or column chromatography process must be performed, the process is complicated, there is a problem in industrialization difficult.

Meanwhile, J. Med. Chem., 1972, Vol. 15, No. 11, and the manufacturing method disclosed in 1150-1154 are as following Reaction Formula 2.

In Scheme 2, Ac represents an acetyl group, and R ¹ represents a hydroxy protecting group.

However, the production method according to the reaction formula 2 is a reaction at a high temperature of 160 ~ 165 ℃ to produce a lot of decomposition products, they are further decomposed into a tar material has a lot of problems in the separation and purification of the target, there are many problems, yield also 74-78% needs improvement. In addition, there is a disadvantage that a separate vacuum distillation apparatus is required to remove acetic acid generated during the reaction.

Furthermore, the N, O- bis (p-nitrophenyl) phosphate used as a catalyst in the preparation method is difficult to industrialize as a very expensive reagent, and the color of the compound of formula 1 ''' Since it is obtained in gray (that is, the purity is low), there is a problem that a separate purification process should be performed when preparing high purity ribavirin using this.

Accordingly, the present inventors have solved the problems of the prior art to develop a method for producing a high-purity ribavirin intermediate in high yield under mild reaction conditions to complete the production process easy to industrialize.

Accordingly, an object of the present invention is to provide a method for preparing the ribavirin intermediate of formula (1).

The present invention is a step of reacting the compound of formula (2) and the compound of formula (3) at 80 ℃ to 120 ℃ in the presence of a catalyst selected from the group consisting of methanesulfonic acid, benzenesulfonic acid and para-toluenesulfonic acid (first process) and crystallization process It relates to a process for the preparation of a compound of formula (1) comprising (second step), which is represented by the following scheme.

R ¹ is a hydroxy protecting group, and R ² represents a C ₁ to C ₄ lower alkyl group.

The compound of Formula 2 and the compound of Formula 3 used as starting materials in the present invention are J. Med. Chem., 1972, Vol. 15, No. 11, It can manufacture by the method disclosed by 1150-1154.

As the hydroxy protecting group of the compound of Formula 2, a protecting group commonly used in the antiviral field, for example, an acetyl group, a benzoyl group, and the like may be used.

As for the equivalence ratio of the compound of Formula 2 and the compound of Formula 3, 1: 1.0-1.2 are preferable. When the compound of formula 3 is used in less than 1 equivalent to the compound of formula 2, unreacted compound of formula 2 may remain, and when the excess is used in excess of 1.2 equivalents, the product, that is, the compound of formula 1 is discolored (yellow). Can be Furthermore, when the compound of Formula 3 remains, it may be converted into 1,2,4-triazole-3-carboxamide in ammonolysis performed during ribavirin preparation and remain as an impurity of ribavirin.

In the production method of the present invention, the higher the reaction temperature of the first step can increase the reaction rate, but considering the quality and yield can be preferably reacted at 80 ℃ ~ 120 ℃, 90 ℃ ~ 100 ℃ It is more preferable to react at.

Methanesulfonic acid, benzenesulfonic acid, or para-toluenesulfonic acid (p-toluenesulfonic acid) used as a catalyst in the production method of the present invention, such as N, O -bis ( Not only is it much cheaper than p-nitrophenyl) phosphate, it does not need to raise the reaction temperature to a high temperature. Among the catalysts that can be used in the preparation method of the present invention, para-toluenesulfonic acid is more preferable because the compound of formula 1 can be obtained in high yield.

In consideration of the yield, the amount of the catalyst usable in the preparation method of the present invention is preferably 0.01 to 0.05 equivalents based on the compound of formula (2).

The first step of the production method according to the present invention can be easily carried out under the reaction conditions, there is no need to use a separate reaction solvent. That is, the compound of Formula 2 and the compound of Formula 3 are melted at the reaction temperature (80 ° C. to 120 ° C.), and the reaction proceeds through the catalyst. The reaction time of the first step is preferably 3 to 6 hours, more preferably melt reaction for 4 to 5 hours.

The production method of the present invention includes a crystallization process. As a solvent which can be used for the crystallization process in the manufacturing method of this invention, alcohol or aqueous solution of alcohols is preferable. As a specific crystallization solvent, methanol, ethanol, butanol, isobutanol, methanol aqueous solution, ethanol aqueous solution, butanol aqueous solution, or isobutanol aqueous solution can be used.

The compound of Chemical Formula 1 prepared by the above method may be prepared with ribavirin according to known methods (US Pat. No. 3,798,209 and J. Med. Chem., 1972, Vol. 15, No. 11, 1150-1154). . That is, when ribavirin is recovered by performing ammonia decomposition and recrystallization from the compound of Formula 1, high purity white ribavirin may be obtained without undergoing further purification and decolorization.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, this does not limit the scope of the invention.

Example 1

26.4 g (0.21 mole) of methyl 1,2,4-triazole-3-carboxylate and 60.2 g (0.19 mole) of β-D-ribofuranosyl-1,2,3,5-tetraacetate were melted. Then 1.1 g of para-toluenesulfonic acid was added. The reaction was carried out for 6 hours while maintaining 85 ± 5 ° C., followed by crystallization with 300.8 ml of methanol to give 1- (2,3,5-tri-O-acetyl-β-D-ribofuranosyl) -1,2,4-triazole. 3-Carboxylic acid methyl ester (57.9 g, yield: 78.9%) was prepared.

NMR (CDCl ₃ ) δ (ppm): 2.12 (t, 9H), 3.99 (s, 3H), 4.25 (m, 1H), 4.48 (m, 2H), 5.57 (t, 1H), 5.76 (q, 1H ), 6.07 (d, 1 H), 8.44 (s, 1 H)

Example 2

26.4 g (0.21 mole) of methyl 1,2,4-triazole-3-carboxylate and 60.2 g (0.19 mole) of β-D-ribofuranosyl-1,2,3,5-tetraacetate were melted. Then 1.1 g of para-toluenesulfonic acid was added. The reaction was carried out for 5 hours while maintaining 95 ± 5 ° C., followed by crystallization with 300.8 mL of methanol to give 1- (2,3,5-tri-O-acetyl-β-D-ribofuranosyl) -1,2,4-triazole. 3-carboxylic acid methyl ester (65.9 g, yield: 90%) was prepared.

Example 3

26.4 g (0.21 mole) of methyl 1,2,4-triazole-3-carboxylate and 60.2 g (0.19 mole) of β-D-ribofuranosyl-1,2,3,5-tetraacetate were melted. Then 1.1 g of para-toluenesulfonic acid was added. After reacting for 3 hours while maintaining 105 ± 5 ° C., it was crystallized from 300.8 ml of methanol to give 1- (2,3,5-tri-O-acetyl-β-D-ribofuranosyl) -1,2,4-triazole. 3-Carboxylic acid methyl ester (58.6 g, yield: 80%) was prepared.

Example 4

24.0 g (0.19 mole) of methyl 1,2,4-triazole-3-carboxylate and 60.2 g (0.19 mole) of β-D-ribofuranosyl-1,2,3,5-tetraacetate were melted. Then 1.1 g of para-toluenesulfonic acid was added. The reaction was carried out for 5 hours while maintaining 95 ± 5 ° C., followed by crystallization with 300.8 ml of methanol to give 1- (2,3,5-tri-O-acetyl-β-D-ribofuranosyl) -1,2,4-triazole. 3-Carboxylic acid methyl ester (60.0 g, yield: 82%) was prepared.

Example 5

A mixture of 28.8 g (0.22 mole) of methyl 1,2,4-triazole-3-carboxylate and 60.2 g (0.19 mole) of β-D-ribofuranosyl-1,2,3,5-tetraacetate was melted. Then 1.1 g of para-toluenesulfonic acid was added. The reaction was carried out for 5 hours while maintaining 95 ± 5 ° C., followed by crystallization with 300.8 ml of methanol to give 1- (2,3,5-tri-O-acetyl-β-D-ribofuranosyl) -1,2,4-triazole. 3-Carboxylic acid methyl ester (66.7 g, yield: 92%) was prepared.

Example 6

26.4 g (0.21 mole) of methyl 1,2,4-triazole-3-carboxylate and 60.2 g (0.19 mole) of β-D-ribofuranosyl-1,2,3,5-tetraacetate were melted. Then para-toluenesulfonic acid 0.36g (0.01 equiv) was added. The reaction was carried out for 5 hours while maintaining 95 ± 5 ° C., followed by crystallization with 300.8 ml of methanol to give 1- (2,3,5-tri-O-acetyl-β-D-ribofuranosyl) -1,2,4-triazole. 3-Carboxylic acid methyl ester (58.9 g, yield: 81%) was prepared.

Example 7

26.4 g (0.21 mole) of methyl 1,2,4-triazole-3-carboxylate and 60.2 g (0.19 mole) of β-D-ribofuranosyl-1,2,3,5-tetraacetate were melted. Then para-toluenesulfonic acid 1.8g (0.05 equiv) was added. The reaction was carried out for 5 hours while maintaining 95 ± 5 ° C., followed by crystallization with 300.8 ml of methanol to give 1- (2,3,5-tri-O-acetyl-β-D-ribofuranosyl) -1,2,4-triazole. 3-carboxylic acid methyl ester (61.7 g, yield: 85%) was prepared.

Example 8

26.4 g (0.21 mole) of methyl 1,2,4-triazole-3-carboxylate and 60.2 g (0.19 mole) of β-D-ribofuranosyl-1,2,3,5-tetraacetate were melted. Then 1.1 g of para-toluenesulfonic acid was added. After reacting for 5 hours while maintaining 95 ± 5 ° C., it was crystallized with 180.5 ml of methanol to give 1- (2,3,5-tri-O-acetyl-β-D-ribofuranosyl) -1,2,4-triazole. 3-Carboxylic acid methyl ester (68.9 g, yield: 95%) was prepared.

Example 9

26.4 g (0.21 mole) of methyl 1,2,4-triazole-3-carboxylate and 60.2 g (0.19 mole) of β-D-ribofuranosyl-1,2,3,5-tetraacetate were melted. Then 1.1 g of para-toluenesulfonic acid was added. The reaction was carried out for 5 hours while maintaining 95 ± 5 ° C., followed by crystallization with 421.1 mL of methanol to give 1- (2,3,5-tri-O-acetyl-β-D-ribofuranosyl) -1,2,4-triazole. 3-Carboxylic acid methyl ester (64 g, yield: 88%) was prepared.

Example 10

1.27 g (0.01 mole) of methyl 1,2,4-triazole-3-carboxylate and 5.04 g of 1- O -acetyl-2,3,5-tri- O -benzoyl-β-D-ribofuranose ( 0.01 mole) of the mixture was added and 0.095 g of para-toluenesulfonic acid was added thereto. The reaction was carried out for 3 hours while maintaining 95 ± 5 ° C., followed by crystallization with 25 ml of methanol to give 1- (2,3,5-tri-O-benzoyl-β-D-ribofuranosyl) -1,2,4-triazole. 3-Carboxylic acid methyl ester (4.85 g, yield: 85%) was prepared.

NMR (CDCl ₃ ) δ (ppm): 3.96 (d, 3H), 4.67-4.80 (m, 2H), 4.87 (m, 1H), 6.11 (t, 1H), 6.16 (q, 1H), 6.34 (d , 1H), 7.38-8.07 (m, 15H), 8.44 (s, 1H)

Example 11

1.41 g (0.01 mole) of ethyl 1,2,4-triazole-3-carboxylate and 3.18 g (0.01 mole) of β-D-ribofuranosyl-1,2,3,5-tetraacetate were melted. Then 0.095 g of para-toluenesulfonic acid was added. The reaction was carried out for 3 hours while maintaining 95 ± 5 ° C., followed by crystallization with 20 ml of methanol to give 1- (2,3,5-tri-O-acetyl-β-D-ribofuranosyl) -1,2,4-triazole. 3-Carboxylic acid ethyl ester (3.27 g, yield: 82%) was prepared.

NMR (CDCl ₃ ) δ (ppm): 1.43 (t, 3H), 2.12 (t, 9H), 4.00 (m, 2H), 4.26 (m, 1H), 4.48 (m, 2H), 5.57 (t, 1H ), 5.77 (q, 1H), 6.10 (d, 1H), 8.50 (s, 1H)

Example 12

1.27 g (0.01 mole) of methyl 1,2,4-triazole-3-carboxylate and 3.18 g (0.01 mole) of β-D-ribofuranosyl-1,2,3,5-tetraacetate were melted. Then methanesulfonic acid 0.048 g was added. The reaction was carried out for 5 hours while maintaining 95 ± 5 ° C., followed by crystallization with 300.8 ml of methanol to give 1- (2,3,5-tri-O-acetyl-β-D-ribofuranosyl) -1,2,4-triazole. 3-Carboxylic acid methyl ester (3.0 g, yield: 79%) was prepared.

Example 13

1.27 g (0.01 mole) of methyl 1,2,4-triazole-3-carboxylate and 3.18 g (0.01 mole) of β-D-ribofuranosyl-1,2,3,5-tetraacetate were melted. Then 0.079 g of benzenesulfonic acid was added. The reaction was carried out for 5 hours while maintaining 95 ± 5 ° C., followed by crystallization with 300.8 ml of methanol to give 1- (2,3,5-tri-O-acetyl-β-D-ribofuranosyl) -1,2,4-triazole. 3-Carboxylic acid methyl ester (3.08 g, yield: 80%) was prepared.

Example 14

1.27 g (0.01 mole) of methyl 1,2,4-triazole-3-carboxylate and 3.18 g (0.01 mole) of β-D-ribofuranosyl-1,2,3,5-tetraacetate were melted. Then 0.076 g of para-toluenesulfonic acid was added. After reacting for 3 hours while maintaining 95 ± 5 ° C., crystallization was performed with 20 ml of ethanol to give 1- (2,3,5-tri-O-acetyl-β-D-ribofuranosyl) -1,2,4-triazole. 3-Carboxylic acid methyl ester (2.92 g, yield: 92%) was prepared.

Example 15

1.27 g (0.01 mole) of methyl 1,2,4-triazole-3-carboxylate and 3.18 g (0.01 mole) of β-D-ribofuranosyl-1,2,3,5-tetraacetate were melted. Then 0.076 g of para-toluenesulfonic acid was added. The reaction was carried out for 3 hours while maintaining 95 ± 5 ° C., followed by crystallization with 20 ml of butanol to yield 1- (2,3,5-tri-O-acetyl-β-D-ribofuranosyl) -1,2,4-triazole. 3-Carboxylic acid methyl ester (2.70 g, yield: 85%) was prepared.

Example 16

1.27 g (0.01 mole) of methyl 1,2,4-triazole-3-carboxylate and 3.18 g (0.01 mole) of β-D-ribofuranosyl-1,2,3,5-tetraacetate were melted. Then 0.076 g of para-toluenesulfonic acid was added. After reacting for 3 hours while maintaining 95 ± 5 ° C., it was crystallized with 20 ml of isobutanol to give 1- (2,3,5-tri-O-acetyl-β-D-ribofuranosyl) -1,2,4-tria. A sol-3-carboxylic acid methyl ester (2.92 g, yield: 92%) was prepared.

Claims (9)

Compound (2) and compound (3) are reacted at 80 ° C to 120 ° C in the presence of a catalyst selected from the group consisting of methanesulfonic acid, benzenesulfonic acid and para-toluenesulfonic acid (first step) and crystallization step (second Process for the preparation of a compound of formula (1) comprising the). R ¹ is a hydroxy protecting group, and R ² represents a C ₁ to C ₄ lower alkyl group. The method of claim 1, wherein the reaction temperature is 90 ℃ to 100 ℃. The process according to claim 1 or 2, wherein the catalyst is para-toluenesulfonic acid. The process according to claim 1 or 2, wherein the amount of the catalyst used is 0.01 to 0.05 equivalents based on the compound of the formula (2). The method according to claim 1 or 2, wherein the equivalent ratio of the compound of Formula 2 to the compound of Formula 3 is 1: 1.0 to 1.2. The production method according to claim 1 or 2, wherein the reaction time of the first step is 3 to 6 hours. The production method according to claim 1 or 2, wherein the crystallization solvent used in the crystallization step is an alcohol or an aqueous solution of alcohols. 8. A process according to claim 7, wherein the crystallization solvent is selected from the group consisting of methanol, ethanol, butanol, isobutanol, aqueous methanol solution, aqueous ethanol solution, aqueous butanol solution, and aqueous isobutanol solution. 9. A process according to claim 8 wherein the crystallization solvent is methanol.